SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction

The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.     

A new genus and two new species of Parastenocarididae (Copepoda: Harpacticoida) from southeastern India

Indocaris gen. nov. with two new species, Indocaris imbricata sp. nov. and Indocaris inopinata sp. nov., and also for the already known Indocaris tirupatiensis (Ranga Reddy 2011a) comb. nov. – all from the groundwaters in peninsular India. The highly diagnostic synapomorphy of the new genus is a composite character associated with the male leg 4 basis: five or six prominent, imbricate, enlarged, petal-like spinules, arranged as a semi-whorl at the insertion of the endopod and increasing in size from internal to external. Another distinctive feature of the same appendage is that its one-segmented endopod is dilated or bulbous in the proximal half, produced distally into an incurved spiniform or horn-like structure about as long as the corresponding first exopodal segment, and ornamented with three or four fine spinules on the subproximal outer margin. The three species also share a unique constellation of other salient morphologic features, which along with the phylogenetic position of Indocaris gen. nov. within the family Parastenocarididae are discussed. Indocaris gen. nov. has closest phylogenetic affinity with the Neotropical Remaneicari Jakobi, 1972. A short note on the ecology and biogeography of the parastenocaridid species of the Indian subcontinent is provided besides a key for their identification.     

A phylogenetic review of the genus Atopobathynella Schminke, 1973 (Crustacea,Malacostraca, Bathynellacea) with three new species from southeastern India

To date, the genus Atopobathynella Schminke, 1973, contains 12 Gondwanan species, including two species from India. Three new species of this genus, viz. A. indica sp. nov., A. nelloreensis sp. nov., and A. inopinata sp. nov., from southeastern India are described herein. The various characters and their states in Atopobathynella, in relation to other parabathynellid species known so far, are discussed; especially its closeness with the genus Kimberleybathynella is highlighted. A morphological phylogenetic analysis of the genus Atopobathynella,along with its closely related genus Kimberleybathynella is also done, and the inter-relationships among the 15 species of Atopobathynella and six species of Kimberleybathynella are deduced, using the software PAUP 4.0b10. This analysis, based on 39 unordered characters, has yielded 23 most parsimonious trees, with a length of 138 steps, a consistency index (CI) of 0.3768, a homoplasy index (HI) of 0.6232, a retention index (RI) of 0.6211, and a rescaled consistency index (RC) of 0.2341. The cladogram thus obtained suggests the grouping of ((A.wattsi, A. glenayleensis), (A. readi, ((((A. gascoyneensis, A. hospitalis), A. hinzeae), (((A. compagana, A. chelifera), A. valdiviana), (((A. operculata, A. paraoperculata), A. nelloreensis), (A. indica, A. inopinata)))), (A. schminkei, (((((K. gigantea, K. kimberleyensis), K. argylensis), K. pleochaeta), K. mandorana), K. hexapoda)))), outgroup). It also shows that the five Indian species are nestled between the Australian Atopobathynella and Kimberleybathynella species. The Indian species appear to be much derived as compared to their Australian counterparts. A brief note on the origin of Bathynellacea is also added at the end.

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